This invention is directed to indane derivatives, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. xcex15xcex21 (VLA-5), xcex14xcex21 (VLA-4) and xcex1Vxcex23]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
Integrins are heterodimeric cell surface receptors consisting of two subunits called xcex1 and xcex2. There are at least fifteen different xcex1-subunits (xcex11-xcex19, xcex1-L, xcex1-M, xcex1-X, xcex1-IIb, xcex1-V and xcex1-E) and at least seven different xcex2 (xcex21-xcex27) subunits. The integrin family can be subdivided into classes based on the xcex2 subunits, which can be associated with one or more xcex1-subunits. The most widely distributed integrins belong to the xcex21 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three xcex1-subunits xcex1-L, xcex1-M or xcex1-X) complexed with the xcex22 protein. The cytoadhesins xcex1-IIbxcex23 and xcex1-Vxcex23, constitute the third class of integrins.
The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor xcex14xcex21 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
The integrin xcex14xcex21 mediates both cell-cell and cell-matrix interactions. Cells expressing xcex14xcex21 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by pro-inflammatory cytokines such as INF-xcex3, TNF-xcex1, IL-1xcex2 and IL-4.
Regulation of xcex14xcex21 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, colitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which xcex14xcex21 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S. M. Wahl et al., J. Clin. Invest., 1994, 94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-xcex14 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J. Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HPxc2xd, an anti-xcex14 monoclonal antibody given intravenously or by aerosol, blocked the late response and the development of airway hyperresponsiveness (W. M. Abraham et al. J. Clin. Invest., 1994, 93 pages 776-787).
We have now found a novel group of indane derivatives which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (xcex14xcex21).
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein:
R1 represents aryl, heteroaryl or a group R3xe2x80x94L2xe2x80x94Ar1xe2x80x94L3xe2x80x94;
R2 represents hydrogen or lower alkyl;
R3 represents aryl or heteroaryl;
R4 is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group, cycloalkyl, heteroaryl, heterocycloalkyl, xe2x80x94S(O)mR5, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4;
R5 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
R6 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R7 is hydrogen, R5 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or xe2x80x94NY3Y4;
R8 is hydrogen or lower alkyl;
R9 and R11 are each independently selected from hydrogen or a group consisting of amino acid side chains, an acidic functional group, R5, xe2x80x94C(xe2x95x90O)xe2x80x94R5, or xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or alkyl substituted by an acidic functional group or by R5, xe2x80x94NY3Y4, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R5, xe2x80x94C(xe2x95x90O)xe2x80x94R12xe2x80x94NH2, xe2x80x94C(xe2x95x90O)xe2x80x94Ar2xe2x80x94NH2, xe2x80x94C(xe2x95x90O)xe2x80x94R12xe2x80x94CO2H, or xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4;
or R7 and R9 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring;
R10 represents C16alkylene, optionally substituted by R4;
R12 is an alkylene chain, an alkenylene chain, or an alkynylene chain;
R13 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
Ar1 represents an optionally substituted saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N;
Ar2 is arylene or heteroaryldiyl;
L1 represents
(i) a direct bond;
(ii) an alkenylene, alkylene or alkynylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, xe2x80x94S(O)mR4, R5, xe2x80x94C(xe2x95x90O)xe2x80x94R5, xe2x80x94C(xe2x95x90O)xe2x80x94OR5, xe2x80x94N(R6)xe2x80x94C(xe2x95x90Z)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or by (b) alkyl substituted by an acidic functional group, or by S(O)mR4, xe2x80x94C(xe2x95x90Z)xe2x80x94NY3Y4 or xe2x80x94NY3Y4;
(iii) a xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94 linkage;
(iv) a xe2x80x94Z1xe2x80x94R10xe2x80x94 linkage;
(v) a xe2x80x94R10xe2x80x94Z1xe2x80x94R10xe2x80x94 linkage;
(vi) a xe2x80x94C(R8)(R11)xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94 linkage; or
(vii) a xe2x80x94L4xe2x80x94L5xe2x80x94L6xe2x80x94 linkage;
L2 represents NR8;
L3 represents an alkylene, alkenylene or alkynylene chain;
L4 and L6 each independently represent a direct bond or an alkylene chain;
L5 represents a cycloalkylene or an indanylene;
Y is carboxy or an acid bioisostere;
Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group xe2x80x94NY1Y2 may form a cyclic amine;
Y3 and Y4 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, xe2x80x94NY1Y2, or one or more xe2x80x94CO2R6 or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 groups; or the group xe2x80x94NY3Y4 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R7; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY5; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;
Y5 is hydrogen, alkyl, aryl, arylalkyl, xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94C(xe2x95x90O)xe2x80x94OR13 or xe2x80x94SO2R13;
Z is O or S;
Z1 is O, S(O)n, NR8, SO2NR8, C(xe2x95x90O)NR8 or C(xe2x95x90O);
m is an integer 1 or 2;
n is zero or an integer 1 or 2;
p is zero or an integer 1 to 4;
the group 
is attached to the benzene ring of the indane system and the group xe2x80x94L1xe2x80x94Y is attached to either ring of the indane system; and
any aryl or heteroaryl moieties present as a group or part of a group may be optionally substituted; but excluding compounds where an oxygen, nitrogen or sulfur atom is attached directly to a carbon carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, protected derivatives of compounds of formula (I) containing one or more acidic functional groups and/or amino-acid side chains, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993, 33, pages 576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995, pages 34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995, 343, pages 105-109 xe2x80x9cTheoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-l-methylpyrazolyl.
xe2x80x9cAcidic functional groupxe2x80x9d means a group with an acidic hydrogen within it. The xe2x80x9cprotected derivativesxe2x80x9d are those where the acidic hydrogen atom has been replaced with a suitable protecting group. For suitable protecting groups see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991. Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Exemplary protected derivatives include esters of carboxy groups (i.e. xe2x80x94CO2R13), ethers of hydroxy groups (i.e. xe2x80x94OR13), thioethers of mercapto groups (i.e. xe2x80x94SR13), and N-benzyl derivatives of imidazoles.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. xe2x80x9cBranchedxe2x80x9d, as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkenyl group, in which the alkenyl group is as described herein. Exemplary alkenylene radicals include vinylene and propylene.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by alkoxy or by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. xe2x80x9cLower alkylxe2x80x9d as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.
xe2x80x9cAlkylenedioxyxe2x80x9d means an xe2x80x94O-alkyl-Oxe2x80x94 group in which the alkyl group is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulfonyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulfonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAlkynylenexe2x80x9d means an aliphatic bivalent radical derived from a C2-6alkynyl group. Exemplary alkynylene radicals include ethynylene and propynylene.
xe2x80x9cAmino acid side chainsxe2x80x9d means the substituent found on the carbon between the amino and carboxy groups in xcex1-amino acids. For examples of xe2x80x9cprotected derivativesxe2x80x9d of amino acid side chains, see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, xe2x80x94NY1Y2, xe2x80x94CONY1Y2, xe2x80x94SO2NY1Y2, xe2x80x94Z2xe2x80x94C2-6alkylene-NY1Y2 {where Z2 is O, NR8 or S(O)n}, xe2x80x94NY1xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94NY1-SO2alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or xe2x80x94NY1Y2.
xe2x80x9cArylalkenylxe2x80x9d means an aryl-alkenyl-group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl-group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cArylalkynylxe2x80x9d means an aryl-alkynyl-group in which the aryl and alkynyl are as previously described. Exemplary arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.
xe2x80x9cArylenexe2x80x9d means an optionally substituted bivalent radical derived from an aryl group. Exemplary arylene groups include optionally substituted phenylene, naphthylene and indanylene.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulfonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulfur, or nitrogen. Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, quinazolinyl and thiazolyl.
xe2x80x9cAzaheteroaryldiylxe2x80x9d means an optionally substituted bivalent radical derived from a heteroaryl group.
xe2x80x9cCyclic aminexe2x80x9d means a 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may optionally contain an additional heteroatom selected from O, S or NY6 (where Y6 is hydrogen, alkyl, arylalkyl, and aryl) and (ii) may be fused to additional aryl or heteroaryl ring to form a bicyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
xe2x80x9cCycloalkenylalkylxe2x80x9d means a cycloalkenyl-alkyl-group in which the cycloalkenyl and alkyl moieties are as previously described. Exemplary cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.
xe2x80x9cCycloalkenylenexe2x80x9d means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkylalkenylxe2x80x9d means a cycloalkyl-alkenyl-group in which the cycloalkyl and alkenyl moieties are as previously described. Exemplary monocyclic cycloalkylalkenyl groups include cyclopentylvinylene and cyclohexylvinylene.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cCycloalkylalkynylxe2x80x9d means a cycloalkyl-alkynyl-group in which the cycloalkyl and alkynyl moieties are as previously described. Exemplary monocyclic cycloalkylalkynyl groups include cyclopropylethynyl, cyclopentylethynyl and cyclohexylethynyl.
xe2x80x9cCycloalkylenexe2x80x9d means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopropylene, cyclopentylene and cyclohexylene.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroaroylaminoxe2x80x9d means a heteroaroyl-NHxe2x80x94 group in which the heteroaryl moiety are as previously described.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above. When R1 is an optionally substituted heteroaryl group this may particularly represent an optionally substituted xe2x80x9cazaheteroarylxe2x80x9d group.
xe2x80x9cHeteroarylalkenylxe2x80x9d means a heteroaryl-alkenyl-group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl-group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeteroarylalkynylxe2x80x9d means a heteroaryl-alkynyl-group in which the heteroaryl and alkynyl moieties are as previously described. Exemplary heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.
xe2x80x9cHeteroaryldiylxe2x80x9d means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur, and optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylsulfonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocycloalkylxe2x80x9d means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY3 and which may optionally be substituted by oxo; (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkyl-group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cHeterocycloalkylenexe2x80x9d means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from O, S or NY6 and is optionally substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when NY6 is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY6 heteroatoms and NY6 is NH by removing a hydrogen atom from both nitrogen atoms.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
Suitable esters of compounds of formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379.
Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety xe2x80x94L1xe2x80x94Y, include lactones, formed by loss of water between said carboxy and hydroxy groups. Examples of lactones include caprolactones and butyrolactones.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent optionally substituted aryl, such as optionally substituted phenyl [preferred optional substituents include one or more groups (e.g. 1 or 2) selected from aryloxy, cyano, halo (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), nitro and perfluoroloweralkyl (e.g. trifluoromethyl)]. R1 especially represents substituted phenyl selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluoropheny,4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl.
R1 may also particularly represent optionally substituted heteroaryl, such as benzoxazole, benzimidazole, isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each optionally substituted by one or more (e.g. 1 or 2) aryl group substituents as described hereinbefore [preferred optional substituents include alkyl-C(xe2x95x90O)xe2x80x94, aryl, cyano, halo, (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), lower alkylsulfonyl, lower alkylthio, nitro and perfluoroloweralkyl (e.g. trifluoromethyl) and xe2x80x94NY1Y2]. R1 especially represents an optionally substituted azaheteroaryl selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl.
R1 may also particularly represent a group R3xe2x80x94L2xe2x80x94Ar1xe2x80x94L3- in which: R3 and L2 are as define above; L3 represents a straight or branched C1-6alkylene chain, more particularly a straight C1-4alkylene chain such as methylene or ethylene, preferably methylene and Ar1 is an 8 to 10 membered bicyclic system 
in which ring 
is a 5 or 6 membered, preferably a 5 membered, heteroaryl ring and ring 
is a 5 or 6 membered heteroaryl ring or a benzene ring, preferably a benzene ring, each ring optionally substituted by one or more (e.g. 1 or 2) xe2x80x9caryl group substituentsxe2x80x9d as defined above and the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage. 
is preferably benzoxazolyl or benzimidazolyl, in which ring 
is optionally substituted by one or more (e.g. 1 or 2) xe2x80x9caryl group substituentsxe2x80x9d as defined above [examples of particular aryl group substituents include C1-4alkyl (e.g. methyl or ethyl), C1-4alkoxy (e.g. methoxy), amino, halogen, hydroxy, C1-4alkylthio, C1-4alkylsulfinyl, C1-4alkylsulfonyl, nitro or trifluoromethyl]. Within R3xe2x80x94L2xe2x80x94Ar1xe2x80x94L3xe2x80x94, L2 is preferably NH and R3 is particularly optionally substituted aryl, such as monosubstituted or disubstituted phenyl, [examples of particular aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y1Y2Nxe2x80x94 (e.g. dimethylamino)].
R2 may particularly represent hydrogen.
R2 may also particularly represent lower alkyl, (e.g. methyl).
L1 may particularly represent an optionally substituted alkylene linkage (e.g. optionally substituted methylene, optionally substituted ethylene or optionally substituted propylene). Preferred optional substituents include lower alkyl, aryl, heteroaryl, xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4. In one preferred embodiment L1 is methylene. In another preferred embodiment L1 is a group 
[where R14 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R14 is hydrogen and R15 represents aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90)xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4], and is more preferably a group 
particularly 
[where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4 or xe2x80x94NY3Y4 or alkyl substituted by carboxy, xe2x80x94OH, xe2x80x94OR13 or xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4]. In another preferred embodiment L1 is a group 
[where R14 is hydrogen or lower alkyl (e.g. methyl) and R16 represents lower alkyl, or where R14 is hydrogen and R16 represents aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4], and is more preferably a group 
particularly 
[where R16 represents xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, or xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4].
L1 may also particularly represent a xe2x80x94L4xe2x80x94L5xe2x80x94L6xe2x80x94 linkage, in which L4 and L6 are independently a direct bond or alkylene (e.g. methylene) and L5 is cycloalkylene, such as cyclopropylene or cyclopentylene, or indanylene.
Y may particularly represent carboxy.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular group of compounds of the invention are compounds of formula (Ia): 
in which R2, R3, L1, L2, L3 and Y are as hereinbefore defined; X is O or NR18 (where R18 is hydrogen or lower alkyl); and R17 is hydrogen, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, xe2x80x94NY1Y2, xe2x80x94CONY1Y2, xe2x80x94SO2NY1Y2, xe2x80x94Z2xe2x80x94C2-6alklene-NY1Y2, xe2x80x94NY1xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94NY1xe2x80x94SO2alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or xe2x80x94NY1Y2 (where Y1, Y2 and Z2 are as defined hereinbefore), and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Compounds of formula (Ia) in which R3 represents optionally substituted aryl, especially monosubstituted or disubstituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y1Y2Nxe2x80x94 (e.g. dimethylamino). R3 especially represents phenyl substituted in at least the 2-position, for example by a C1-4alkyl group such as methyl.
Compounds of formula (Ia) in which L2 represents NH are preferred.
Compounds of formula (Ia) in which R17 represents hydrogen, halo (e.g. chloro), lower alkyl (e.g. methyl or ethyl) or lower alkoxy (e.g. methoxy) are preferred.
Compounds of formula (Ia) in which L3 represents a straight or branched C1-6alkylene chain, especially a straight C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ia) in which R2 represents hydrogen are preferred.
Compounds of formula (Ia) in which R2 represents lower alkyl, (e.g. methyl) are also preferred.
Compounds of formula (Ia) in which L1 represents an optionally substituted alkylene linkage (e.g. optionally substituted methylene, optionally substituted ethylene or optionally substituted propylene) are preferred. Preferred optional substituents include lower alkyl, aryl, heteroaryl, xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or alkyl substituted by carboxy (or anacid bioisostere), xe2x80x94ZH xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4. In one preferred embodiment L1 is methylene. In another preferred embodiment L1 is a group 
[where R14 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R14 is hydrogen and R15 represents aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3T4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4], and is more preferably a group 
particularly 
[where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4 or xe2x80x94NY3Y4 or alkyl substituted by carboxy, xe2x80x94OH, xe2x80x94OR13 or xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4]. In another preferred embodiment L1 is a group 
[where R14 is hydrogen or lower alkyl (e.g. methyl) and R16 represents lower alkyl, or where R14 is hydrogen and R16 represents aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4], and is more preferably a group 
particularly 
[where R16 represents xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, or xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4].
Compounds of formula (Ia) in which L1 represents a xe2x80x94L4xe2x80x94L5xe2x80x94L6xe2x80x94 linkage, in which L4 and L6 are independently a direct bond or alkylene (e.g. methylene) and L5 is cycloalkylene, such as cyclopropylene or cyclopentylene, or indanylene are also preferred.
Compounds of formula (Ia) in which Y represents carboxy are preferred.
A preferred group of compounds of the invention are compounds of formula (Ia) in which: R2 is hydrogen or lower alkyl (e.g. methyl); R3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C14alkyl); R17 is hydrogen, chloro, C1-4alkyl, or C1-4alkoxy; L1 is methylene; L2 is NH; L3 is a straight C1-4alkylene chain, especially methylene; X is O; Y is carboxy; the group 
is attached at the benzoxazole ring 6a position; the nitrogen atom of the 
linkage is attached to the indane ring 5 or 6 position; and the xe2x80x94L1xe2x80x94Y group is attached to the indane ring 1 or 2 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another preferred group of compounds of the invention are compounds of formula (Ia) in which: R2 is hydrogen or lower alkyl (e.g. methyl); R3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C1-4alkyl); R17 is hydrogen, chloro, C1-4alkyl, or C1-4alkoxy; L1 is methylene; L2 is NH; L3 is a straight C1-4alkylene chain, especially methylene; X is NR18 (especially NH); Y is carboxy; the group 
is attached at the benzimidazole ring 5a or 6a position; the nitrogen atom of the 
linkage is attached to the indane ring 5 or 6 position; and the xe2x80x94L1xe2x80x94Y group is attached to the indane ring 1 or 2 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another particular group of compounds of the invention are compounds of formula (Ib): 
in which R2, R3, L1, L2, L3 and Y are as hereinbefore defined; X is O or NR18 (where R18 is hydrogen or lower alkyl); and R17 is hydrogen, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, xe2x80x94NY1Y2, xe2x80x94CONY1Y2, xe2x80x94SO2NY1Y2, xe2x80x94Z2xe2x80x94C2-6alkylene-NY1Y2, xe2x80x94NY1xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94NY1xe2x80x94SO2alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or xe2x80x94NY1Y2 (where Y1, Y2 and Z2 are as defined hereinbefore), and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Compounds of formula (Ib) in which R3 represents optionally substituted aryl, especially monosubstituted or disubstituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y1Y2Nxe2x80x94(e.g. dimethylamino). R3 especially represents phenyl substituted in at least the 2-position, for example by a C1-4alkyl group such as methyl.
Compounds of formula (Ib) in which L2 represents NH are preferred.
Compounds of formula (Ib) in which R17 represents hydrogen, halo (e.g. chloro), lower alkyl (e.g. methyl or ethyl) or lower alkoxy (e.g. methoxy) are preferred.
Compounds of formula (Ib) in which L3 represents a straight or branched C1-6alkylene chain, especially a straight C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ib) in which R2 represents hydrogen are preferred.
Compounds of formula (Ib) in which R2 represents lower alkyl, (e.g. methyl) are also preferred.
Compounds of formula (Ib) in which L1 represents an optionally substituted alkylene linkage (e.g. optionally substituted methylene, optionally substituted ethylene or optionally substituted propylene) are preferred. Preferred optional substituents include lower alkyl, aryl, heteroaryl, xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4. In one preferred embodiment L1 is a group 
[where R14 is hydrogen or lower alkyl (e.g. methyl) and R15 represents hydrogen or lower alkyl, or where R14 is hydrogen and R15 represents aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4], and is more preferably a group 
particularly 
[where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4 or xe2x80x94NY3Y4 or alkyl substituted by carboxy, xe2x80x94OH, xe2x80x94OR13 or xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4]. In another preferred embodiment L1 is a group 
[where R14 is hydrogen or lower alkyl (e.g. methyl) and R16 represents lower alkyl, or where R14 is hydrogen and R16 represents aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4, xe2x80x94NY3Y4 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R7)xe2x80x94C(R8)(R9)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an an acid bioisostere), xe2x80x94ZH, xe2x80x94ZR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4], and is more preferably a group 
particularly 
[where R16 represents xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, or xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4].
Compounds of formula (Ib) in which L1 represents a xe2x80x94L4xe2x80x94L5xe2x80x94L6xe2x80x94 linkage, in which L4 and L6 are independently a direct bond or alkylene (e.g. methylene) and L5 is cycloalkylene, such as cyclopropylene or cyclopentylene, or indanylene are also preferred.
Compounds of formula (Ib) in which Y represents carboxy are preferred.
A preferred group of compounds of the invention are compounds of formula (Ib) in which: R2 is hydrogen or lower alkyl (e.g. methyl); R3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C1-4alkyl); R17 is hydrogen, chloro, C1-4alkyl, or C1-4alkoxy; L1 is a 
group particularly a 
group, where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4 or xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94OH, xe2x80x94OR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4; L2 is NH; L3 is a straight or branched C1-4alkylene chain, especially methylene; X is O; Y is carboxy; the group 
is attached at the benzoxazole ring 6a position; the nitrogen atom of the 
linkage is attached to the indane ring 4 position; and the xe2x80x94L1xe2x80x94Y group is attached to the indane ring 7 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another preferred group of compounds of the invention are compounds of formula (Ib) in which: R2 is hydrogen or lower alkyl (e.g. methyl); R3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C1-4alkyl); R17 is hydrogen, chloro, C1-4alkyl, or C1-4alkoxy; L1 is a 
group, particularly 
[where R16 represents xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, or xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4]; L2 is NH; L3 is a straight C1-4alkylene chain, especially methylene; X is O; Y is carboxy; the group 
is attached at the benzoxazole ring 6a position; the nitrogen atom of the 
linkage is attached to the indane ring 4 position; and the xe2x80x94L1xe2x80x94Y group is attached to the indane ring 7 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another preferred group of compounds of the invention are compounds of formula (Ib) in which: R2 is hydrogen or lower alkyl (e.g. methyl); R3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C1-4alkyl); R17 is hydrogen, chloro, C1-4alkyl, or C1-4alkoxy; L1 is a 
group particularly a 
group, where R15 represents hydrogen, lower alkyl, aryl, heteroaryl, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94N(R6)xe2x80x94C(xe2x80x94O)xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4 or xe2x80x94NY3Y4, or alkyl substituted by carboxy (or an acid bioisostere), xe2x80x94OH, xe2x80x94OR13, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 or xe2x80x94NY3Y4;]; L2 is NH; L3 is a straight C1-4alkylene chain, especially methylene; X is NR18 (especially NH); Y is carboxy; the group 
is attached at the benzimidazole ring 5a or 6a position; the nitrogen atom of the 
linkage is attached to the indane ring 4 position; and the xe2x80x94L1xe2x80x94Y group is attached to the indane ring 7 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another preferred group of compounds of the invention are compounds of formula (Ib) in which: R2 is hydrogen or lower alkyl (e.g. methyl); R3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C1-4alkyl); R17 is hydrogen, chloro, C1-4alkyl, or C1-4alkoxy; L1 is a 
group, particularly 
[where R16 represents xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4, or xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R4]; L2 is NH; L3 is a straight C1-4alkylene chain, especially methylene; X is NR18 (especially NH); Y is carboxy; the group 
is attached at the benzimidazole ring 5a or 6a position; the nitrogen atom of the 
linkage is attached to the indane ring 4 position; and the xe2x80x94L1xe2x80x94Y group is attached to the indane ring 7 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Particular compounds of the invention of formula I(a) are selected from the compounds formed by joining the carbon atom (C*) of one of the fragments (A1 to A36) shown in Table 1 to the nitrogen atom (N*) of one of the fragments (B5 to B12) shown in Table 2, and joining the carbon atom (C*) of one of the fragments (B5 to B12) shown in Table 2 to the carbon atom (C*) of one of the acidic fragments (C1 to C3) depicted in Table 3.
Particular compounds of the invention of formula I(b) are selected from the compounds formed by joining the carbon atom (C*) of one of the fragments (A1 to A36) shown in Table 1 to the nitrogen atom (N*) of one of the fragments (B1 to B4) shown in Table 2, and joining the carbon atom (C*) of one of the fragments (B1 to B4) shown in Table 2 to the carbon atom (C*) of one of the acidic fragments (C3 to C32) depicted in Table 3.
Examples of compounds in accordance with the present invention are those derived from all combinations of fragments xe2x80x9cAxe2x80x9d, xe2x80x9cBxe2x80x9d, and xe2x80x9cCxe2x80x9d, and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Thus, for example, in the above list the compound denoted as A1-B1-C5 is the product of the combination of group A1 in Table 1 and B1 in Table 2 and C5 in Table 3, namely 
A preferred compound of the invention is:
3-{7-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-4-yl}-butyric acid;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21) according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of xcex14xcex21 mediated cell adhesion. For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds may be useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of formula (I), wherein R1, R2 and L1 are as hereinbefore defined, and where Y is carboxy, may be prepared by hydrolysis of esters of formula (I), wherein R1, R2 and L1 are as hereinbefore defined and Y is a xe2x80x94CO2R19 group (in which R19 is alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient temperature to about reflux temperature. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example compounds of formula (I), wherein R1, R2 and L1 are as hereinbefore defined, and where Y is carboxy, may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I), wherein R1, R2 and L1 are as hereinbefore defined and Y is a xe2x80x94CO2R19 group (in which R19 is tert-butyl), using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
As another example compounds of formula (I), wherein R1, R2 and L1 are as hereinbefore defined, and where Y is carboxy, may be prepared by hydrogenation of compounds of formula (I) wherein R1, R2 and L1 are as hereinbefore defined and Y is a xe2x80x94CO2R19 group (in which R19 is arylmethyl, e.g. benzyl). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. This reaction is most suitable for compounds of formula (I) where L1 does not contain carbon-carbon multiple bonds.
In a process A compounds of formula (I), containing an amide bond may be prepared by coupling of an acid (or an acid halide) with an amine to give an amide bond using standard peptide coupling procedures as described hereinafter.
As an example of process A, esters of formula (I), wherein R1, R2 and L1 are as hereinbefore defined, and Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined), may be prepared by reacting a compound of formula (II): 
wherein R1 is as hereinbefore defined and X1 is a hydroxy group, or a halogen, preferably chlorine, atom with an amine of formula (III): 
wherein R2, R19 and L1 are as hereinbefore defined, the group R2xe2x80x94NHxe2x80x94 is attached to the benzene ring of the indane system and the group xe2x80x94L1xe2x80x94CO2R19 is attached to either ring of the indane system, using standard coupling conditions. For example when X1 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures for example coupling in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide), at room temperature. When X1 is a halogen atom the acylation reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
As another example of process A, compounds of formula (I) wherein R1, R2 and L1 are as hereinbefore defined, and Y is carboxy, may be prepared by:
(i) treating bromo-Wang resin (4-bromomethylphenoxylated styrene/divinylbenzene copolymer) with an acid of formula (IV) wherein R2 and L1 are as hereinbefore defined, R20 is a suitable imino-protecting group, such as 9H-fluoren-9-ylmethoxylcarbonyl, the group 
is attached to the benzene ring of the indane system and the group xe2x80x94L1xe2x80x94CO2H is attached to either ring of the indane system, in the presence of a tertiary amine, such as diisopropylethylamine, and cesium iodide, in an inert solvent, such as dimethylformamide, at a temperature at about room temperature, to give Resin A: 
where 
represents the polymeric core comprising polystyrene crosslinked with 1% to 2% divinylbenzene;
(ii) treatment of Resin A with piperidine in an inert solvent, such as dimethylformamide, and at a temperature at about room temperature to give Resin B: 
wherein R2, L1 and 
are as hereinbefore defined;
(iii) Reaction of Resin B with compounds of formula (II) wherein R1 and X1 are as hereinbefore defined, using standard coupling procedures (for example those described hereinabove), to give Resin C: 
wherein R1, R2 L1 and 
are as hereinbefore defined;
(iv) treatment of Resin C with trifluoroacetic acid in an inert solvent, such as dichloromethane, and at a temperature at about room temperature.
As another example of process A, esters of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 contains a xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R4 group (in which R6 and R4 are as hereinbefore defined) may be prepared by reaction of the corresponding compounds of formula (I) wherein R1, R2 and Y are as hereinbefore defined and L1 contains a xe2x80x94NH(R6) group (in which R6 is as hereinbefore defined) with acids (or acid chlorides) of formula (V): 
wherein R4 and X1 are as hereinbefore defined, using standard coupling conditions, for example those described hereinbefore.
Esters of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 contains a xe2x80x94NHR6 group (in which R6 is alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl), may be prepared by alkylation of the corresponding derivatives of formula (I) where L1 contains a xe2x80x94NH2 group, with the appropriate alkyl (or arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl) halide. The alkylation may for example be carried out in the presence of a base, such as an alkali metal hydride, e.g. sodium hydride, in dimethylformamide, or dimethyl sulfoxide, at a temperature from about 0xc2x0 C. to about 100xc2x0 C.
Esters of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 contains a xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR4 group (in which R6 and R4 are as hereinbefore defined), may be prepared from the corresponding derivatives of formula (I) where L1 contains a xe2x80x94NHR6 group (in which R6 is as hereinbefore defined) by reaction with compounds of formula R4Oxe2x80x94C(xe2x95x90O)xe2x80x94X2 wherein R4 and X2 is a halogen, preferably chlorine atom, or xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94OR4 in the presence of a suitable base, such as triethylamine or pyridine, and at a temperature from about 0xc2x0 C. to about room temperature.
Esters of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 is 
may be prepared by hydrogenation of the corresponding derivatives of formula (I), where L1 is 
The reaction may be carried out in the presence of formic acid and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, at a temperature at about 60xc2x0 C. The reaction may conveniently be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
Esters of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 is a 
linkage, may also be obtained from the racemic mixture following standard recrystallisation of a suitable salt (for example recrystallisation of the tartrate salt), or by the application of standard enzymatic resolution procedures (for example those described by Soloshonok, V. A., et. al., Tetrahedron: Asymmetry 6 (1995) 7, 1601-1610).
Esters of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 is a 
linkage, may be prepared by reacting an ester of formula (I), wherein R1 and R2 are as hereinbefore defined, Y is a xe2x80x94CO2R19 group (in which R19 is as hereinbefore defined) and L1 is a xe2x80x94CHxe2x95x90CHxe2x80x94 linkage, with an alkali metal hydride, such as sodium hydride, in an inert solvent, e.g. tetrahydrofuran, and at a temperature at about room temperature, and subsequent reaction with the anion derived from treating dibenzylamine, or (S)-N-benzyl-xcex1-methylbenzylamine, with butyllithium, at a temperature at about xe2x88x9278xc2x0 C.
Lactones of formula (I) wherein R1 and R2 are as hereinbefore defined and the moiety xe2x80x94L1xe2x80x94Y is 
may be prepared by the selective reduction (using for example a borane derivative or lithium borohydride) of compounds of formula (I) wherein R1 and R2 are as hereinbefore defined and the moiety xe2x80x94L1xe2x80x94Y is 
(in which R21 is lower alkyl) followed by spontaneous cyclisation of the intermediate hydroxy compound. The reduction can be achieved by the application or adaptation of the procedures described by C. J. Francis and J. Bryan Jones, J. Chem. Soc, Chem. Commun., 1984, (9), 579-58, J. Hiratake et al, J. Chem. Soc, Perkin Trans, 1987, 1 (5), 1053-8 L. K. P. Lamet al, J. Org. Chem. (1986), 51(11), 2047-50.
Lactones of formula (I) wherein R1 and R2 are as hereinbefore defined and the moiety xe2x80x94L1xe2x80x94Y is 
may be similarly prepared from compounds of formula (I) wherein R1 and R2 are as hereinbefore defined and the moiety xe2x80x94L1xe2x80x94Y is 
According to a further feature of the present invention, compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of formula (I), wherein R1, R2 and L1 are as hereinbefore defined, and Y is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, may be prepared by reacting compounds of formula (I), wherein R1, R2 and L1 are as hereinbefore defined and Y is carboxy, with hydroxylamine using standard peptide coupling procedures such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, in an inert solvent such as dichloromethane or tetrahydrofuran and at a temperature at about room temperature. The coupling may also be carried out using 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in dichloromethane at room temperature. The preparation may also be carried out using an O-protected hydroxylamine such as O-(trimethylsilyl)hydroxylamine, O-(t-butyldimethylsilyl)-hydroxylamine, or O-(tetrahydropyranyl)hydroxylamine followed by treatment with acid.
As another example of the interconversion process, compounds of formula (I) containing sulfoxide linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulfate in a medium such as aqueous methanol, buffered to about pH 5, at temperatures between about 0xc2x0 C. and room temperature. This latter method is preferred for compounds containing an acid-labile group.
As another example of the interconversion process, compounds of formula (I) containing sulfone linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 or sulfoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
As another example of the interconversion process, compounds of formula (I), wherein R1, R2 and Y are as hereinbefore defined, and L1 is optionally substituted alkylene, may be prepared by hydrogenation of the corresponding compounds of formula (I) in which L1 is the corresponding optionally substituted alkenylene. The hydrogenation may be carried out using hydrogen (optionally under pressure) in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (I), wherein R1 and R2 are as hereinbefore defined, L1 is an alkylene linkage substituted by xe2x80x94CONY3Y4 and Y is carboxy, may be prepared by reacting compounds of formula (I), wherein R1 and R2 are as hereinbefore defined, L1 is an alkylene linkage substituted by xe2x80x94CO2H and Y is carboxy, with an anhydride, such as trifluoroacetic anhydride, in an inert solvent e.g. tetrahydrofuran, followed by treatment with an amine HNY3Y4.
As another example of the interconversion process, compounds of formula (I) wherein R1 and R2 are as hereinbefore defined, L1 is a 
linkage and Y is carboxy, may be prepared by (i) reacting an ester of formula (I) wherein R1 and R2 are as hereinbefore defined, L1 is a xe2x80x94CHxe2x95x90CHxe2x80x94 linkage and Y is xe2x80x94CO2R19 (in which R19 is as hereinbefore defined) with dimethyl malonate, in the presence of an alkali metal alkoxide, such as sodium methoxide, in methanol and at a temperature at about reflux temperature and (ii) treatment of the resulting compounds of formula (I) wherein R1 and R2 are as hereinbefore defined, L1 is a 
linkage and Y is xe2x80x94CO2R19 with hydrochloric acid at reflux temperature.
As another example of the interconversion process, compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides. The oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90xc2x0 C. Alternatively, the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. The oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60xc2x0 C.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Acids of formula (II) wherein R1 is a group R3xe2x80x94L2xe2x80x94Ar1xe2x80x94L3xe2x80x94[in which R3 and L3 are as defined hereinbefore, L2 is NH, Ar1 is 
(in which R17 is as hereinbefore defined] and X1 is a hydroxy group may be prepared by: (i) reaction of compounds of formula (1): 
wherein R17, R19 and L3 are as hereinbefore defined and X is O, with isothiocyanates of formula R3xe2x80x94Nxe2x95x90Sxe2x95x90O (in which R3 is as hereinbefore defined) in ethanol and at room temperature; (ii) reaction with a carbodiimide, such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in ethanol and at a temperature from about room temperature to about reflux temperature and (iii) acidic or alkaline hydrolysis of the esters where for example R19 is alkyl, hydrogenolysis of the esters where for example R19 is benzyl or acid catalysed removal of the tert-butyl group of the esters where R19 is tert-butyl using standard reaction conditions for example those described hereinbefore.
Acids of formula (II) wherein R1 is a group R3xe2x80x94L2xe2x80x94Ar1xe2x80x94L3xe2x80x94 (in which R3 and L3 are as hereinbefore defined, Ar1 is 
(in which R17 is as hereinbefore defined), L2 is NH and X1 is hydroxy may be similarly prepared from compounds of formula (1) wherein R17, R19 and L3 are as hereinbefore defined and X is NH.
Acid chlorides of formula (II) wherein R1 is as hereinbefore defined and X1 is a chlorine atom may be prepared from the corresponding acids of formula (II) wherein R1 is as hereinbefore defined and X1 is hydroxy, by the application of standard procedures for the conversion of acids to acid chlorides for example by reaction with oxalyl chloride.
Compounds of formula (III) wherein R19 and L1 are as hereinbefore defined, R2 is hydrogen, the R2xe2x80x94NHxe2x80x94 group is attached to the benzene ring of the indane system and the group xe2x80x94L2xe2x80x94Y is attached to either ring of the indane system, may be prepared by reduction of the corresponding nitro compounds of formula (2): 
wherein R19 and L1 are as defined hereinbefore, the nitro group is attached to the benzene ring of the indane system and the group xe2x80x94L2xe2x80x94Y is attached to either ring of the indane system. For compounds of formula (III) in which R19 is alkyl and L1 is an optionally substituted alkylene linkage the reduction may conveniently be carried out by hydrogenation of the corresponding nitro compounds of formula (2) wherein R19 is as just defined and L1 is the corresponding optionally substituted alkylene or alkenylene linkage, using standard hydrogenation conditions, for example those described hereinbefore. For compounds of formula (III) in which R19 is benzyl the reduction may conveniently be carried out using iron powder and ammonium chloride, in aqueous ethanol at a temperature at about reflux, or tin (II) chloride in the presence of hydrochloric acid, at a temperature up to about 80xc2x0 C.
Compounds of formula (III) wherein R19 and L1 are as hereinbefore defined, R2 is hydrogen, the R2xe2x80x94NHxe2x80x94 group is attached to the benzene ring of the indane system and the group xe2x80x94L2xe2x80x94CO2R19 is attached to either ring of the indane system may be prepared by reaction of compounds of formula (3): 
wherein R2, R19 and L1 are as just defined and R20 is an acid-labile protecting group (e.g. acetyl), the 
group is attached to the benzene ring of the indane system and the group xe2x80x94L2xe2x80x94CO2R19 is attached to either ring of the indane system, with hydrochloric acid and at a temperature at about reflux temperature followed by re-esterification using standard esterification procedures [for example when R19 is alkyl the esterification may conveniently be prepared following reaction with an alkyl alcohol (e.g. methanol) in the presence of an acid catalyst, such as hydrogen chloride or sulfuric acid at a temperature from about room temperature to about reflux temperature]. This method is particularly suitable for the preparation of compounds of formula (III) where R2 is hydrogen and both the R2xe2x80x94NHxe2x80x94 and the L1xe2x80x94CO2R19 group are attached to the benzene ring of the indane system.
Compounds of formula (III) wherein R19 and L1 are as hereinbefore defined and R2 is methyl may be prepared by treatment of compounds of formula (III) wherein R19 and L1 are as hereinbefore defined and R2 is hydrogen with formic acetic anhydride followed by reduction with lithium aluminium hydride according to the procedure described by L. G. Humber L G et al, J Med Chem., 1971, 14, page 982.
Compounds of formula (2) wherein R19 and L1 are as defined hereinbefore may be prepared by esterification of acids of formula (4): 
wherein L1 is as defined hereinbefore, the nitro group is attached to the benzene ring of the indane system and the group xe2x80x94L2xe2x80x94CO2H is attached to either ring of the indane system, using standard esterification procedures as described hereinbefore.
Compounds of formula (4) wherein L1 are as defined hereinbefore and the nitro group is attached to the benzene ring of the indane system, may be prepared by nitration of compounds of formula (5): 
wherein L1 are as defined hereinbefore and the group xe2x80x94L2xe2x80x94CO2H is attached to either ring of the indane system, with concentrated nitric acid in the presence of acetic acid and acetic anhydride at a temperature at about 5xc2x0 C. This method is particularly suitable for the preparation of compounds of formula (4) where the xe2x80x94L1xe2x80x94CO2H group are attached to the cyclopentyl ring of the indane system.
Compounds of formula (IV) wherein R2, R20 and L1 are as defined hereinbefore, may be prepared from the corresponding esters of formula (3) wherein R2, R19, R20 and L1 are as hereinbefore defined using standard reaction conditions, for example those described hereinbefore (acidic or alkaline hydrolysis of the esters where for example R19 is alkyl, hydrogenolysis of the esters where for example R19 is benzyl or acid catalysed removal of the tert-butyl group of the esters where R19 is tert-butyl).
Compounds of formula (3) wherein R2 and R19 are as hereinbefore defined, R20 is a suitable protecting group (e.g. acetyl) and L1 is alkenylene, alkynylene or cycloalkenylene attached to the benzene ring of the indane system, may be prepared by reaction compounds of formula (6): 
wherein R2 and R20 are as just defined and X3 is a halogen atom attached to the benzene ring of the indane system, with a compound of formula (7)
R21xe2x80x94CO2R19xe2x80x83xe2x80x83(7)
wherein R19 is as hereinbefore defined and R21 is alkenyl, alkynyl or cycloalkenyl. When X3 is a bromine or iodine atom the reaction may be conveniently carried out in the presence of palladium acetate, a triarylphosphine, such as tri-o-tolylphosphine, and a tertiary amine, such as tributylamine, at a temperature up to about 110xc2x0 C. This reaction is particularly suitable for the preparation of esters of formula (I) in which L1 is vinylene. When X3 is a chlorine atom the reaction may be conveniently carried out in the presence of sodium iodide, nickel bromide, palladium(0) bis(dibenzylideneacetone), a triarylphosphine, such as tri-o-tolylphosphine, and a tertiary amine, such as tributylamine, at a temperature up to about 110xc2x0 C.
Compounds of formula (3) wherein R2 and R20 are as defined hereinbefore, R19 is alkyl and L1 is alkylene or cycloalkylene, may be prepared by hydrogenation of the corresponding compounds of formula (3) wherein L1 is alkenylene, alkynylene or cycloalkenylene, using standard hydrogenation conditions as described hereinbefore.
Compounds of formula (3) wherein R2, R19 and R20 are as defined hereinbefore and L1 is 
may be prepared by reaction of compounds of formula (8): 
wherein R2, R20 and Ar1 are as defined hereinbefore, X4 is a bromine or chlorine atom, with the anion derived from reaction of (2R) -(xe2x88x92)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with butyllithium according to the method described by D. L. Boger and D. Yohannes, J. Org. Chem. [JOCEAH], 1990, 55, for the preparation of compound 31 on page 6010.
Compounds of formula (5) wherein L1 is methylene, substituted by xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R4, and attached to the indane ring may be prepared by the application or adaptation of the methods described by Burk et. al., J. Amer. Chem. Soc., 1995, 117, pages 9375-9376.
Compounds of formula (5) wherein L1 is alkylene attached to the indane ring may be prepared by: (i) reaction of indanone with the appropriate ester of formula (9):
Brxe2x80x94L1xe2x80x94CO2R21xe2x80x83xe2x80x83((9)
wherein R21 is as hereinbefore defined and L1 is alkylene in the presence of zinc according to the procedure described by Campbaell et. al., Org. Prep. Proced. Int., 1991, 23, pages 660-665; (ii) dehydration of the resulting hydroxy-indane in the presence of sulfuric acid; (iii) hydrogenation of the resulting indene.
Compounds of formula (6) wherein R2 is hydrogen, R20 is acetyl, X3 is a halogen atom and both the X3 and 
groups are attached to the benzene ring of the indane system, may be prepared by the application or adaptation of the methods described by A. Courtin, Helv. Chim. Acta., 1980, 63, pages 2280-2286.